Attitudes toward offering genetic counseling for psychiatric conditions among genetics healthcare practitioners in the United Kingdom: A qualitative study.

Psychiatric conditions affect a large proportion of the population. High heritability estimates have been reported for commonly diagnosed conditions, suggesting both environmental factors and genetic variation significantly contribute to the chance of psychiatric outcomes. Despite growing interest in the provision and receipt of genetic counseling services for these conditions, such specialized interventions are not routinely available in most healthcare systems, including in the United Kingdom (UK). This study examined the attitudes of fourteen National Health Service employed genetic counselors and clinical geneticists, from seven regional genetic centers, toward offering psychiatric genetic counseling (PGC) in the UK. A qualitative methodology was adopted and individual semi-structured interviews were conducted either by telephone or face-to-face, audio recorded, transcribed in full and analyzed using thematic analysis. Participants' attitudes were organized under three themes: "Demand," "Readiness to Provide Support," and "Patient Experience." Participants cited key informational and resource needs which included increased workforce capacity, access to further psychological support for patients and more knowledge about the following: specific genes involved, available genetic testing, recurrence/occurrence risk figures, clinical manifestations, diagnostic criteria, patient concerns associated with the impact of psychiatric conditions and interpersonal skills. While some participants appreciated the value of PGC, some reported apprehension and raised concerns around a lack of available genetic testing, the perceived utility of current management options, and a potential negative psychological impact of PGC. This study identified important barriers to the delivery of PGC in the UK by genetics healthcare practitioners. Our findings highlight the importance of a collaborative, multidisciplinary approach to delivering this intervention and the need for additional training. Further research is required to better understand demand for, nature of, and barriers to provision of PGC in the UK, particularly in terms of genetic counselors' perceptions of their role.

Evidence of epigenetic admixture in the Colombian population.

DNA methylation (DNAm) measured in lymphoblastoid cell lines has been repeatedly demonstrated to differ between various human populations. Due to the role that DNAm plays in controlling gene expression, these differences could significantly contribute to ethnic phenotypic differences. However, because previous studies have compared distinct ethnic groups where genetic and environmental context are confounded, their relative contribution to phenotypic differences between ethnicities remains unclear. Using DNAm assayed in whole blood and colorectal tissue of 132 admixed individuals from Colombia, we identified sites where differential DNAm levels were associated with the local ancestral genetic context. Our results are consistent with population specific DNAm being primarily driven by between population genetic differences in cis, with little environmental contribution, and with consistent effects across tissues. The findings offer new insights into a possible mechanism driving phenotypic differences among different ethnic groups, and could help explain ethnic differences in colorectal cancer incidence.

The heritability and patterns of DNA methylation in normal human colorectum.

DNA methylation (DNAm) has been linked to changes in chromatin structure, gene expression and disease. The DNAm level can be affected by genetic variation; although, how this differs by CpG dinucleotide density and genic location of the DNAm site is not well understood. Moreover, the effect of disease causing variants on the DNAm level in a tissue relevant to disease has yet to be fully elucidated. To this end, we investigated the phenotypic profiles, genetic effects and regional genomic heritability for 196080 DNAm sites in healthy colorectum tissue from 132 unrelated Colombian individuals. DNAm sites in regions of low-CpG density were more variable, on average more methylated and were more likely to be significantly heritable when compared with DNAm sites in regions of high-CpG density. DNAm sites located in intergenic regions had a higher mean DNAm level and were more likely to be heritable when compared with DNAm sites in the transcription start site (TSS) of a gene expressed in colon tissue. Within CpG-dense regions, the propensity of the DNAm level to be heritable was lower in the TSS of genes expressed in colon tissue than in the TSS of genes not expressed in colon tissue. In addition, regional genetic variation was associated with variation in local DNAm level no more frequently for DNAm sites within colorectal cancer risk regions than it was for DNAm sites outside such regions. Overall, DNAm sites located in different genomic contexts exhibited distinguishable profiles and may have a different biological function.

Imputation of DNA Methylation Levels in the Brain Implicates a Risk Factor for Parkinson's Disease.

Understanding how genetic variation affects intermediate phenotypes, like DNA methylation or gene expression, and how these in turn vary with complex human disease provides valuable insight into disease etiology. However, intermediate phenotypes are typically tissue and developmental stage specific, making relevant phenotypes difficult to assay. Assembling large case-control cohorts, necessary to achieve sufficient statistical power to assess associations between complex traits and relevant intermediate phenotypes, has therefore remained challenging. Imputation of such intermediate phenotypes represents a practical alternative in this context. We used a mixed linear model to impute DNA methylation (DNAm) levels of four brain tissues at up to 1826 methylome-wide sites in 6259 patients with Parkinson's disease and 9452 controls from across five genome-wide association studies (GWAS). Six sites, in two regions, were found to associate with Parkinson's disease for at least one tissue. While a majority of identified sites were within an established risk region for Parkinson's disease, suggesting a role of DNAm in mediating previously observed genetic effects at this locus, we also identify an association with four CpG sites in chromosome 16p11.2. Direct measures of DNAm in the substantia nigra of 39 cases and 13 control samples were used to independently replicate these four associations. Only the association at cg10917602 replicated with a concordant direction of effect (P = 0.02). cg10917602 is 87 kb away from the closest reported GWAS hit. The employed imputation methodology implies that variation of DNAm levels at cg10917602 is predictive for Parkinson's disease risk, suggesting a possible causal role for methylation at this locus. More generally this study demonstrates the feasibility of identifying predictive epigenetic markers of disease risk from readily available data sets.

Complex variation in measures of general intelligence and cognitive change.

Combining information from multiple SNPs may capture a greater amount of genetic variation than from the sum of individual SNP effects and help identifying missing heritability. Regions may capture variation from multiple common variants of small effect, multiple rare variants or a combination of both. We describe regional heritability mapping of human cognition. Measures of crystallised (gc) and fluid intelligence (gf) in late adulthood (64-79 years) were available for 1806 individuals genotyped for 549,692 autosomal single nucleotide polymorphisms (SNPs). The same individuals were tested at age 11, enabling us the rare opportunity to measure cognitive change across most of their lifespan. 547,750 SNPs ranked by position are divided into 10, 908 overlapping regions of 101 SNPs to estimate the genetic variance each region explains, an approach that resembles classical linkage methods. We also estimate the genetic variation explained by individual autosomes and by SNPs within genes. Empirical significance thresholds are estimated separately for each trait from whole genome scans of 500 permutated data sets. The 5% significance threshold for the likelihood ratio test of a single region ranged from 17-17.5 for the three traits. This is the equivalent to nominal significance under the expectation of a chi-squared distribution (between 1 df and 0) of P<1.44×10(-5). These thresholds indicate that the distribution of the likelihood ratio test from this type of variance component analysis should be estimated empirically. Furthermore, we show that estimates of variation explained by these regions can be grossly overestimated. After applying permutation thresholds, a region for gf on chromosome 5 spanning the PRRC1 gene is significant at a genome-wide 10% empirical threshold. Analysis of gene methylation on the temporal cortex provides support for the association of PRRC1 and fluid intelligence (P = 0.004), and provides a prime candidate gene for high throughput sequencing of these uniquely informative cohorts.